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Genetic engineering is a promising tool to repair genetic disorders, improve graft function or to reduce immune responses towards the allografts. Ex vivo organ perfusion systems have the potential to mitigate ischemic-reperfusion injury, prolong preservation time or even rescue organ function. We aim to combine both technologies to develop a modular platform allowing the genetic modification of vascularized composite (VC) allografts. Rat hind limbs were perfused ex vivo under subnormothermic conditions with lentiviral vectors. Specific perfusion conditions such as controlled pressure, temperature and flow rates were optimized to support the genetic modification of the limbs. Genetic modification was detected in vascular, muscular and dermal limb tissues. Remarkably, skin follicular and interfollicular keratinocytes as well as endothelial cells (ECs) showed stable transgene expression. Furthermore, levels of injury markers such as lactate, myoglobin and lactate dehydrogenase (LDH) as well as histological analyses showed that ex vivo limb perfusion with lentiviral vectors did not cause tissue damage and limb cytokine secretion signatures were not significantly affected. The use of ex vivo VC perfusion in combination with lentiviral vectors allows an efficient and stable genetic modification of limbs representing a robust platform to genetically engineer limbs towards increasing graft survival after transplantation.

Patients with kidney failure depend on transplantation as the only curative option. Xenotransplantation re-emerged as a promising alternative to enlarge the available organ pool. However, the success of xenotransplantation depends on the design and selection of specific genetic modifications and on the development of robust assays allowing for a precise assessment of tissue-specific immune responses. Nevertheless, cell-based assays are often compromised by the low proliferative capacity of primary cells. Proximal tubular epithelial cells (PTECs) play a crucial role in kidney function. Here, we immortalized PTEC (imPTEC) by overexpression of simian virus 40 T large antigen. imPTEC showed typical morphology, phenotype, and functionality, but maintained steady cell cycling rates. Furthermore, SLA class I and class II transcript levels were reduced by up to 85% after transduction with lentiviral vectors encoding for shRNAs targeting β2-microglobulin and the class II transactivator. This contributed to reduce xenogeneic T-cell cytotoxicity (P = 0.0069) and decrease pro-inflammatory cytokine secretion such as IL-6 and IFN-γ. This study showed the feasibility to generate highly proliferative renal tubular cells and the development of tissue-specific immunomonitoring assays. Silencing SLA expression on PTEC demonstrated to be an effective strategy to prevent xenogeneic cellular immune responses and may strongly support graft survival after xenotransplantation.

Genetic engineering is a promising tool to repair genetic disorders, improve graft function, or reduce immune responses toward allografts.

Humanized mouse models generated with human hematopoietic stem cells (HSCs) and reconstituting the human immune system (HIS-mice) are invigorating preclinical testing of vaccines and immunotherapies. We have recently shown that human engineered dendritic cells boosted bonafide human T and B cell maturation and antigen-specific responses in HIS-mice. Here, we evaluated a cell-free system based on in vivo co-delivery of lentiviral vectors (LVs) for expression of a human leukocyte antigen (HLA-DRA*01/ HLA-DRB1*0401 functional complex, “DR4”), and a LV vaccine expressing human cytokines (GM-CSF and IFN-α) and a human cytomegalovirus gB antigen (HCMV-gB). Humanized NOD/Rag1null/IL2Rγnull (NRG) mice injected by i.v. with LV-DR4/fLuc showed long-lasting (up to 20 weeks) vector distribution and expression in the spleen and liver. In vivo administration of the LV vaccine after LV-DR4/fLuc delivery boosted the cellularity of lymph nodes, promoted maturation of terminal effector CD4+ T cells, and promoted significantly higher development of IgG+ and IgA+ B cells. This modular lentigenic system opens several perspectives for basic human immunology research and preclinical utilization of LVs to deliver HLAs into HIS-mice.

MALT1 is a key mediator of NF-κB signaling and a main driver of B-cell lymphomas. Remarkably, MALT1 is expressed in the majority of pancreatic ductal adenocarcinomas (PDACs) as well, but absent from normal exocrine pancreatic tissue. Following, MALT1 shows off to be a specific target in cancer cells of PDAC without affecting regular pancreatic cells. Therefore, we studied the impact of pharmacological MALT1 inhibition in pancreatic cancer and showed promising effects on tumor progression. Mepazine (Mep), a phenothiazine derivative, is a known potent MALT1 inhibitor. Newly, we described that biperiden (Bip) is a potent MALT1 inhibitor with even less pharmacological side effects. Thus, Bip is a promising drug leading to reduced proliferation and increased apoptosis in PDAC cells in vitro and in vivo. By compromising MALT1 activity, nuclear translocation of c-Rel is prevented. c-Rel is critical for NF-κB-dependent inhibition of apoptosis. Hence, off-label use of Bip or Mep represents a promising new therapeutic approach to PDAC treatment. Regularly, the Anticholinergicum Bip is used to treat neurological side effects of Phenothiazines, like extrapyramidal symptoms.

The purpose of this paper is to improve our understanding of how South African economic actors react to the gradual entry of non-South African BRICS firms in their established business areas. Throughout the twentieth century, South Africa’s trade and investment activities were conducted overwhelmingly with Western countries. However, the end of apartheid coincided with significant shifts as new players had a wider and growing presence. South Africa entering the BRICS alliance is symbolic of the change. Ease of entry into the South African economy has increased greatly. South African businesses in key subsectors in the mining and capital equipment industry have had to adapt to new players, and find space in new structures, value chains and initiatives. This paper presents the results of this research activity from the perspective of the South African political economy. Practice-oriented research investigated how six local companies forge new partnerships and how well South African firms adapt and cope with an altered and often unstable environment. It assumed that entrepreneurial activity is not autonomous but takes place within a larger organisational framework. Entrepreneurial activity facilitates the effective exploitation of particular niches and relationships with service providers.

© 2014 © 2014 The South African Institute of International Affairs. Framed by the 5th BRICS Summit in South Africa in March 2013 this analysis examines economic ‘South South’ linkages on a company level. A qualitative case study focuses on a small number of private corporations operating in the South African mining and minerals sector. It looks at their reactions to increasingly competitive markets in the regions of Southern and West Africa thus on their agency defined as the ability to act in complex uncertainty. Findings present how the South African cases' engagements with strategically selected partner companies from the other BRICS economies can succeed. This contribution attempts to examine entrepreneurial rationale that can be taken as anecdotal evidence of a new ‘economic diplomacy’ at corporate level. The examples illustrate how agency enables certain adaptations of strategies for creating competitive synergies from collaboration with new actors from the other BRICS economies in Africa.

The relationship of cooperation and competition between South African private businesses and Asian companies has become more complex in the last 20 years. With South Africa joining what became BRICS in early 2011 it now represents the African continent with its growing market potential. However South African medium and large size companies (SA MLCs) seem to perceive the positioning of BRIC businesses rather as a challenge than as a window of opportunity. This article identifies the need for a deeper understanding of the adaptive capacity and practices of South African private companies which play a significant role for job creation in South Africa. What we hereby present is in fact a first foray into companies’ pragmatic engagements for achieving relative stability in increasing competitive markets. This is consequent of empirical research in its initial stages. The theoretical framework applied picks up recent debates revolving around the ‘practice turn.’ First evidence from business corroborates an alternative field specific approach referring to Fligstein’s relational sociology of markets and Thévenot’s concept of pragmatic regimes of justification.

Every BRICS nation has grown a multitude of successful companies over the past two decades. At the fifth BRICS Summit in Durban in 2013, South Africa demonstrated an entrepreneurial enthusiasm for collaboration within the BRICS (Brazil, Russia, India, China, South Africa). High priority was accorded to examining how to create intra-BRICS opportunities on the African continent to benefit all partners, including African businesses.